The purpose of this grant is to develop novel inhibitors of herpes simplex virus (HSV) replication. HSV is the etiologic agent of a number of clinically significant human diseases including genital herpes, herpes facialis and labialis, acute and recurrent keratoconjunctivitis, meningo-encephalitis, and chronic mucocutaneous infections of immunocompromised individuals. Three viral genes have been selected as targets for the initial phase of the program, because the encoded proteins are thought to serve bifunctional roles in HSV replication. Antisense oligonucleotides may inhibit the production of these proteins while avoiding the adverse side effects observed with current nucleoside analog therapies for HSV infection. Thus, the identification of inhibitory oligonucleotides will provide an improved topical therapy for the estimated 130 million people who suffer from genital and mucocutaneous HSV infections. In the initial phase of the project, the feasibility of this approach wig be examines Dy designing, synthesizing, and testing antisense oligonucleotides against HSV replication in vitro.